This invention relates to a process for producing an optically active tropinonemonocarboxylic acid ester derivative which is an intermediate for synthesis of alkaloids having the same optically active tropane skeleton as the skeleton of cocaine having affinity for dopamine receptors or dopamine transporters as a pharmacological action.
In recent years, as the span of human life extends, patients with psychoneurotic diseases such as Parkinson""s disease, Alzheimer""s disease, etc. increase rapidly with a growth of the aged population, and the investigation of the cause of these psychoneurotic diseases and the establishment of therapeutic methods for them are accelerated at present. Parkinson""s disease is chronic and progressive and their main symptoms are tremor, myoatrophy, akinesia, and impediment in posture maintenance. This diseases is caused by the loss of the balance between dopaminergic nervous system and cholinergic nervous system which is attributable to a marked decrease in the dopamine content of the striata body and substantia nigra of extrapyramidal motor system.
Therefore, in order to treat, for example, Parkinson""s disease, it is necessary to supply the dopamine deficiency or control the cholinergic nervous system in an excited state.
On the other hand, cocaine is an alkaloid contained in leaves of, for example, Erythroxylon coca of South America growth, and was clinically used as a local anesthetic in 1877 for the first time by Koller. Cocaine has recently been found to have affinity for dopamine receptors or dopamine transporters, and it is being revealed that cocaine derivatives are useful as various tracer ligands. The basic structure of cocaine is its tropane skeleton. When cocaine is used as a starting material for a cocaine derivative, an optically active tropane skeleton having the same absolute configuration as that of the skeleton of natural (xe2x88x92)-cocaine can easily be derived as shown in the following reaction scheme A (A. P. Kozikowski, J. Med. Chem. 1995, 38, 3086): 
As derivatives thus synthesized by using (xe2x88x92)-cocaine as a starting material, there are, for example, 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)-tropane (xcex2-CIT; U.S. Pat. No. 5,310,912) and its derivative 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)-8-(3-fluoropropyl)-nortropane (xcex2-CIT-FP; WO 96/39198) which have affinity for dopamine transporters and are noted as diagnotic drugs for Parkinson""s disease; (xe2x88x92)-ferruginine, an agonist for nicotine-like acetylcholine receptors; and (+)-knightinol.
Cocaine, however, is designated as a narcotic because of problems such as drug dependence, and there are various difficulties in obtaining and handling cocaine. Therefore, it is desirable to develop an economical and easy synthetic process of a cocaine analogue.
Attempts have been made to synthesize cocaine analogues since early times. Robinson et al. synthesized tropinone by condensing succindialdehyde with methyl amine and ethyl acetonedicarboxylate (Robinson R., J. Chem. Soc. 1917, 762-768). In 1991, anhydroecgonine methyl ester was synthesized from vinyldiazomethane and a pyrrole derivative by using a rhodium catalyst (Hum M. L. Davies et al., J. Org. Chem. 1991, 56, 5696-5700, Japanese Patent Application Kohyo No. 7-504665). The cocaine analogues synthesized by these processes are not optically active. As the synthesis of an optically active cocaine analogue, there is a case where (R)-allococaine or (R)-allopseudococaine was synthesized by saponifying cocaine or using as an intermediate, (R)-pseudoecgonine methyl ester obtained by optical resolution of (RS)-2-carbomethoxy-3-tropinone (F. I. Carroll et al., J. Med. Chem. 1991, 34, 883-886).
An example of enantio-selective asymmetric reaction without optical resolution is the syntheses of an optically active tropinonemonocarboxylic acid ester and anhydroecgonine methyl ester by the asymmetric synthetic reaction of tropinone with chiral lithium amide (Majewski M., J. Org. Chem. 1995, 60, 5825-5830). The thus obtained anhydroecgonine methyl ester, however, has an absolute configuration different from that of anhydro-ecgonine methyl ester derived from natural (xe2x88x92)-cocaine.
In view of such conditions, the present invention is intended to provide a process for producing an optically active tropinonemonocarboxylic acid ester derivative useful as an intermediate for synthesizing an optically active tropane derivative without using cocaine as a starting material.
The present invention relates to a process for producing an optically active tropinonemonocarboxylic acid ester derivative which comprises subjecting a tropinonedicarboxylic acid ester derivative represented by the following formula (1): 
wherein Rxe2x80x2 is an alkyl group, an aralkyl group or an amino-protecting group selected from lower aliphatic acyl groups, aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, and R is an alkyl group or an aralkyl group, to asymmetric dealkoxycarbonylation in the presence of an enzyme to obtain an optically active tropinonemonocarboxylic acid ester derivative represented by the following formula (2): 
wherein R and Rxe2x80x2 are as defined above.
The present invention also relates to a process for producing an optically active tropinonemonocarboxylic acid ester derivative which comprises reacting succindi-aldehyde represented by the following formula (3): 
with an organic amine represented by the following formula (4):
Rxe2x80x3xe2x80x94NH2xe2x80x83xe2x80x83(4)
wherein Rxe2x80x3 is an alkyl group or an aralkyl group, and an acetonedicarboxylic acid ester represented by the following formula (5): 
wherein R is an alkyl group or an aralkyl group; if necessary, converting the substituent derived from the substituent Rxe2x80x3 of the organic amine of the formula (4) to an amino-protecting group; thereby obtaining a tropinonedicarboxylic acid ester derivative represented by the following formula (1): 
wherein Rxe2x80x2 is an alkyl group, an aralkyl group or an amino-protecting group selected from lower aliphatic acyl groups, aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, and R is an alkyl group or an aralkyl group; and then subjecting the tropinonedicarboxylic acid ester derivative to asymmetric dealkoxycarbonylation in the presence of an enzyme to obtain an optically active tropinonemonocarboxylic acid ester derivative represented by the following formula (2): 
wherein R and Rxe2x80x2 are as defined above.
The present invention further relates to a process for producing an optically active anhydroecgonine carboxylic acid ester derivative which comprises converting the substituent Rxe2x80x2 and/or substituent R of the optically active tropinonemonocarboxylic acid ester derivative of the above formula (2) to another substitu-ent or other substituents if necessary, reducing the oxo group at the 3-position of this derivative, and then dehydrating the resulting compound to obtain an optically active anhydroecgonine carboxylic acid ester derivative represented by the following formula (6): 
wherein R and Rxe2x80x2 are as defined above.
The optically active tropinonemonocarboxylic acid ester derivative obtained by the production process of the present invention is useful as an intermediate for synthesizing a cocaine analogue without using cocaine as a starting material, said cocaine analogue having a tropane skeleton, the basic ring structure of cocaine, and having the same optical activity as that of a cocaine analogue derived from natural (xe2x88x92)-cocaine.
The tropinonedicarboxylic acid ester derivative of the above formula (1), the starting material in the production process of the present invention, may be synthesized by the process shown in the following reaction scheme B: 
As shown in the reaction scheme B, the tropinonedicarboxylic acid ester derivative of the formula (1) is synthesized by reacting succindialdehyde of the formula (3) with an organic amine of the formula (4) and an acetonedicarboxylic acid ester of the formula (5) and, if necessary, converting the substituent derived from the substituent Rxe2x80x3 of the organic amine of the formula (4) to an amino-protecting group.
Succindialdehyde of the formula (3) is a well-known compound and is obtained, for example, by hydrolyzing 2,5-dimethoxytetrahydrofuran.
The organic amine of the formula (4) and the acetonedicarboxylic acid ester of the formula (5) are also well-known compounds and are synthesized by per se well-known processes. Each of the substituent Rxe2x80x3 of the organic amine of the formula (4) and the substituent R of the acetonedicarboxylic acid ester of the formula (5) is an alkyl group or an aralkyl group. Specific examples of the alkyl group are alkyl groups of 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group, etc. Specific examples of the aralkyl group are aralkyl groups of 7 to 10 carbon atoms, such as benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, etc.
The reaction of succindialdehyde of the formula (3) with the organic amine of the formula (4) and the acetonedicarboxylic acid ester of the formula (5) is per se well known. For example, when each of the substitu-ents R and Rxe2x80x3 is a methyl group (Me), a methanolic solution containing dimethyl 1,3-acetonedicarboxylate is added to a methanol solution of succindialdehyde in an ice bath under a nitrogen atmosphere, a methanolic solution containing methylamine is added dropwise thereto in an ice bath and stirred overnight, and the solvent is distilled off to obtain dimethyl 8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1a: Rxe2x80x2=Me and R=Me in the formula (1)) in a yield of 70-90 mol %.
The thus obtained tropinonedicarboxylic acid ester derivative may be subjected as it is to the asymmetric dealkoxycarbonylation explained hereinafter. If necessary, the alkyl or aralkyl group as the substituent Rxe2x80x2 of the amino group at the 8-position derived from the substituent Rxe2x80x3 of the organic amine of the formula (4) may be converted to an amino-protecting group. The amino-protecting group includes lower aliphatic acyl groups, aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, etc. As the lower aliphatic acyl groups, there may be exemplified lower aliphatic acyl groups of 2 to 7 carbon atoms, such as acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group, etc. As the aromatic acyl groups, there may be exemplified aromatic acyl groups of 7 to 11 carbon atoms, such as benzoyl group, naphthanoyl group, etc. As the lower alkoxy-carbonyl groups, there may be exemplified lower alkoxycarbonyl groups of 2 to 7 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, etc. As the aralkyloxycarbonyl groups, there may be exemplified aralkyloxycarbonyl groups of 8 or 9 carbon atoms, such as benzyloxycarbonyl group, methoxybenzyloxycarbonyl group, etc. As the aryloxycarbonyl groups, there may be exemplified aryloxycarbonyl groups of 7 to 11 carbon atoms, such as phenoxycarbonyl group, naphthoxycarbonyl group, etc. As the tri-lower-alkylsilyl groups, there may be exemplified tri(C1-C6)alkylsilyl groups such as trimethylsilyl group, triethylsilyl group, tributylsilyl group, etc.
The conversion to any of these amino-protecting groups is a per se well-known reaction.
A desired optically active tropinonemonocarboxylic acid ester derivative of the formula (2) is obtained by subjecting the thus obtained tropinonedicarboxylic acid ester derivative of the formula (1) to asymmetric dealkoxycarbonylation using an enzyme, as shown in the following reaction scheme C: 
In this case, the optically active tropinonemonocarboxylic acid ester derivative of the formula (2) obtained by enzyme-catalyzed asymmetric dealkoxycarbonylation of the ester group at the 2- or 4-position of the tropinonedicarboxylic acid ester derivative of the formula (1) is effectively used as an intermediate for synthesis of various cocaine analogues.
The yield of the optically active tropinonemonocarboxylic acid ester derivative of the formula (2) from the asymmetric dealkoxycarbonylation of the tropinonedicarboxylic acid ester derivative of the formula (1) and its optical purity are affected by the kinds of the substituent Rxe2x80x2 of the amino group at the 8-position, the substituent R of the ester group at the 2- or 4-position and the enzyme used. In particular, the kinds of the substituent of the ester group and the enzyme used have a great influence.
As the enzyme used in the present invention, there may be exemplified liver esterases such as porcine liver esterase (PLE), rabbit liver esterase, horse liver esterase, etc.; and baker""s yeast (B.Y.). In particular, porcine liver esterase (PLE) and baker""s yeast (B.Y.) are suitably used.
A preferable combination of the substituent Rxe2x80x2 of the amino group at the 8-position and the substituent R of the ester group at the 2- or 4-position of the tropinonedicarboxylic acid ester derivative of the formula (1) is a combination wherein R is an alkyl group of 1 to 6 carbon atoms and Rxe2x80x2 is an aralkyl group, a lower aliphatic acyl group, an aromatic acyl group, an aryloxycarbonyl group or a tri-lower-alkylsilyl group; a combination wherein R is an alkyl group of 2 to 6 carbon atoms and Rxe2x80x2 is an aralkyloxycarbonyl group; or a combination wherein each of R and Rxe2x80x2 is an aralkyl group. More specifically, preferable is a combination wherein R is an alkyl group of 1 to 6 carbon atoms selected from methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group and hexyl group, and Rxe2x80x2 is an aralkyl group of 7 to 10 carbon atoms selected from benzyl group, phenethyl group, phenylpropyl group and phenylbutyl group; a combination wherein R is an alkyl group of 2 to 6 carbon atoms selected from ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group and hexyl group, and Rxe2x80x2 is an aralkyloxycarbonyl group of 8 or 9 carbon atoms selected from benzyloxycarbonyl group and methoxybenzyl-oxycarbonyl group; or a combination wherein each of R and Rxe2x80x2 is an aralkyl group of 7 to 10 carbon atoms selected from benzyl group, phenethyl group, phenylpropyl group and phenylbutyl group.
Preferable examples of the tropinonedicarboxylic acid ester derivative of the formula (1) which have any of these combinations are the following compounds:
dimethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1b: Rxe2x80x2=Bn and R=Me in the formula (1)),
diethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1c: Rxe2x80x2=Bn and R=Et in the formula (1)),
diisopropyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1d: Rxe2x80x2=Bn and R=i-Pr in the formula (1)),
dibutyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1e: Rxe2x80x2=Bn and R=n-Bu in the formula (1)),
dibenzyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1f: Rxe2x80x2=Bn and R=Bn in the formula (1)), and
diethyl 8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1g: Rxe2x80x2=Z and R=Et in the formula (1)).
The asymmetric dealkoxycarbonylation is carried out at pH 7-9 and at a temperature of approximately 10-40xc2x0 C. As a buffer solution, there are used phosphate buffer solutions, toluene-phosphate buffer solutions, Tris buffer solutions, HEPES buffer solutions, etc. The amount of the enzyme used is varied depending on the kind of the enzyme. For example, the amount of PLE is 500-5,000 units/mmol substrate, and the amount of B.Y. is 1-5 g/mmol substrate.
The optically active tropinonemonocarboxylic acid ester derivative of the formula (2) is obtained by the asymmetric dealkoxycarbonylation. When the compounds described above as preferable examples of the tropinone-dicarboxylic acid ester derivative of the formula (1) are used, the following corresponding compounds of the formula (2) are obtained:
methyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2b: Rxe2x80x2=Bn and R=Me in the formula (2)),
ethyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2c: Rxe2x80x2=Bn and R=Et in the formula (2)),
isopropyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2d: Rxe2x80x2=Bn and R=i-Pr in the formula (2)),
butyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2e: Rxe2x80x2=Bn and R=n-Bu in the formula (2)),
benzyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2f: Rxe2x80x2=Bn and R=Bn in the formula (2)), and
ethyl (1R,5S)-8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2g: Rxe2x80x2=Z and R=Et in the formula (2)).
The optically active tropinonemonocarboxylic acid ester derivative obtained according to the present invention is a mixture of three kinds of isomers, i.e., enol form and two keto forms as shown in the following reaction scheme D. This fact can be confirmed by NMR data of the derivative. 
Therefore, the optical purity of the optically active tropinonemonocarboxylic acid ester derivative obtained according to the present invention was measured by converting said derivative to an xcex1,xcex2-unsaturated ester compound, a single compound by reduction and dehydration as shown in the following reaction scheme E, and then subjecting this ester compound to HPLC using a chiral column: 
Specifically, for example, each of the above-exemplified compounds (xe2x88x92)-2c, (xe2x88x92)-2d, (xe2x88x92)-2e and (xe2x88x92)-2f, i.e., optically active tropinonemonocarboxylic acid ester derivatives obtained according to the present invention is converted to the above-exemplified compound (xe2x88x92)-2b, a methyl ester compound by transesterification, which is then converted to the xcex1,xcex2-unsaturated ester compound A by reduction and dehydration, and the compound A is subjected to HPLC using a chiral column (eluent: hexane:2-propanol=100:1), whereby the optical purity was measured. The optical purity of the above-exemplified compound (xe2x88x92)-2g having a benzyloxycarbonyl group as a protecting group for the amino group may be measured by removing the benzyloxycarbonyl group with trifluoroacetic acid (TFA), benzylating the resulting compound into the above-exemplified compound (xe2x88x92)-2c, and then converting the compound (xe2x88x92)-2c to the a unsaturated ester compound A in the manner shown in the reaction scheme E.
xcex1,xcex2-Unsaturated ester compound A in dl-form used as a reference standard compound was synthesized by hydrolyzing dimethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1b: Rxe2x80x2=Bn and R=Me in the formula (1)) with LiOH, decarboxylating the hydrolysate into tropinonemonoester with 2N-HCl, and reducing this compound with NaBH4, followed by dehydration.
As to the absolute configuration, as shown in the following reaction scheme F, each of the above-exemplified compounds (xe2x88x92)-2c, (xe2x88x92)-2d, (xe2x88x92)-2e, (xe2x88x92)-2f and (xe2x88x92)-2g, i.e., the optically active tropinonemonocarboxylic acid ester derivatives obtained according to the present invention, is converted to methyl 8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((+)-B), and this compound is reduced and then dehydrated to obtain anhydroecgonine methyl ester ((xe2x88x92)-C). On the other hand, as shown in the following reaction scheme G, natural (xe2x88x92)-cocaine was converted to anhydroecgonine methyl ester. When the anhydroecgonine methyl ester obtained from each of the above-exemplified compounds was compared with that obtained from natural (xe2x88x92)-cocaine, their directions of optical rotation were the same (xe2x88x92) in the case of all the above-exemplified ompounds. It was confirmed by this fact that the absolute configuration of the optically active tropinonemonocarboxylic acid ester derivative obtained by the enzyme reaction according to the present invention is identical to that of (xe2x88x92)-cocaine. 
The thus obtained optically active tropinonemonocarboxylic acid ester derivative according to the present invention may be converted to an optically active anhydroecgonine carboxylic acid ester derivative represented by the following formula (6): 
wherein R and Rxe2x80x2 are as defined above, by converting the substituent Rxe2x80x2 and/or the substituent R to another substituent or other substituents if necessary, and then reducing the oxo group at the 3-position, followed by dehydration. Such an optically active anhydroecgonine carboxylic acid ester derivative is useful as an intermediate for synthesis of drugs such as 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)tropane (xcex2-CIT) and its derivatives including xcex2-CIT-FP and tropane alkaloids such as (xe2x88x92)-ferruginine.
(+)-Ferruginine is an alkaloid isolated from Darlingiana ferruginea and D. darlingiana, and its enantiomer (xe2x88x92)-ferruginine is known as an agonist for nicotine-like acetylcholine receptors. The (+)-form and (xe2x88x92)-form of ferruginine have been synthesized from L-glutamic acid (H. Rapoport et al., J. Org. Chem. 1996, 61, 314).
For example, using butyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2e: Rxe2x80x2=Bn and R=n-Bu in the formula (2)), an optically active tropinonemonocarboxylic acid ester derivative obtained according to the present invention, (xe2x88x92)-ferruginine may be synthesized as shown in the=Boc and R=Me in the formula (6)), an optically active anhydroecgonine carboxylic acid ester derivative. The methyl ester group and Boc group of the optically active anhydroecgonine carboxylic acid ester derivative obtained are replaced by an acetyl group and a methyl group, respectively, by well-known methods to obtain a desired compound (xe2x88x92)-ferruginine.
Physiological properties such as optical rotation, 1H-NMR, etc. of the optically active anhydroecgonine carboxylic acid ester derivative obtained above, i.e., methyl (1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((xe2x88x92)-6a), agree with the values described in a reference (H. Rapoport et al., J. Org. Chem. 1996, 61, 314). Thus, the synthesis of (xe2x88x92)-ferruginine has been achieved.
As shown in the following reaction scheme I, each of the drug 2xcex2-carbomethoxy-3xcex2-(4-iodophenyl)-tropane (xcex2-CIT) and its derivative xcex2-CIT-FP may be synthesized from methyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2b: Rxe2x80x2=Bn and R=Me in the formula (2)), an optically active tropinonemonocarboxylic acid methyl ester obtained according to the present invention. following reaction scheme H. 
At first, butyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2e) is converted to methyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2b: Rxe2x80x2=Bn and R=Me in the formula (2)) by transesterification, and then the benzyl group as a protecting group for the amino group is removed by catalytic reduction and a t-butoxycarbonyl (Boc) group is introduced. The resulting keto-ester, methyl (1R,5S)-8-t-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2h: Rxe2x80x2=Boc and R=Me in the formula (2)) is reduced with NaBH4 and then dehydrated to obtain methyl (1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((xe2x88x92)-6a: Rxe2x80x2 
In detail, the benzyl group of methyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2b) is replaced by a methyl group to obtain methyl (1R,5S)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((+)-2a: Rxe2x80x2=Me and R=Me in the formula (2)). Thereafter, the obtained compound may be converted to methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((xe2x88x92)-6b: Rxe2x80x2=Me and R=Me in the formula (6)), optically active anhydroecgonine methyl ester by reduction with NaBH4 followed by dehydration. From this optically active anhydroecgonine methyl ester, xcex2-CIT or xcex2-CIT-FP may be synthesized according to a well-known process.
As exemplified above, the optically active tropinonemonocarboxylic acid ester derivative of the formula (2) obtained by the process of the present invention may be converted to an optically active anhydroecgonine carboxylic acid ester derivative of the formula (6) which is useful as an intermediate for synthesis of drugs, by converting the substituent Rxe2x80x2 and/or the substituent R to another substituent or other substituents if necessary, and then reducing the oxo group at the 3-position, followed by dehydration. In this case, the conversion of the substituent Rxe2x80x2 and/or the substituent R to another substituent or other substituents may be carried out by a well-known reaction such as transesterification as is clear from the example described above. The reduction and dehydration are per se well-known reactions. For example, the reduction may be carried out with NaBH4 or PtO2, and the dehydration may be carried out with trifluoroacetic anhydride (TFAA), POCl3 or the like.
The anhydroecgonine carboxylic acid ester derivative obtained according to the present invention is optically active and is very useful as an intermediate for synthesis of drugs.
In general, the optical purity of an optically active substance used as a drug is very important in imparting a specific pharmacological effect and preventing side effects, etc. Easy production of an optically active tropinonemonocarboxylic acid ester derivative having a high optical purity has been successfully achieved by carrying out the asymmetric dealkoxycarbonylation of a tropinonedicarboxylic acid ester derivative according to the present invention. In addition, it has become possible to obtain easily an anhydroecgonine ester derivative having a very high optical purity by synthesizing an anhydroecgonine carboxylic acid ester derivative by the use of the optically active tropinonemonocarboxylic acid ester derivative having a high optical purity. Moreover, it is possible to synthesize a crystalline anhydroecgonine ester derivative. Furthermore, it has become possible to produce easily a crystalline anhydroecgonine ester derivative having a much higher optical purity by purification by recrystallization.
For example, when as shown in the following reaction scheme J, methyl (1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((xe2x88x92)-6a: Rxe2x80x2=Boc and R=Me in the formula (6)) was synthesized by converting the substituent of the amino group of methyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((xe2x88x92)-2b: Rxe2x80x2=Bn and R=Me in the formula (2)) to a Boc group, and reducing the resulting compound, followed by dehydration, colorless needles (mp 79-80xc2x0 C.) were obtained. Thus, it has become very easy to increase the optical purity by recrystallization. Crystalline methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((xe2x88x92)-6b: Rxe2x80x2=Me and R=Me in the formula (6)) having a very high optical purity may be synthesized by replacing the Boc group of the compound (xe2x88x92)-6a by a methyl group. 
The present invention is illustrated in further detail with the following examples, which should not be construed as limiting the scope of the invention.
Methods for measuring physical properties of substances obtained, common solvents, etc. are as follows.
(1) Melting point: Measured by using a micro hot-stage apparatus (Yanagimoto) and a directly heated capillary melting point apparatus (Mitamura Riken Industries, Ltd.).
(2) 1H-NMR: Measured with a Varian XL-300 spectrometer. Chemical shift values are expressed in ppm by using tetramethylsilane (TMS) as an internal standard.
(3) Optical rotation: Measured with Horiba Sepa-200.
(4) Infrared spectrum: Measured with Jasco IR-810 and SHIMADZU FTIR-8300. Frequencies are expressed in cmxe2x88x921.
(5) Mass spectrum: Measured with a JEOL AJMX-SX102AQQ mass spectrometer and a JEOL JMS-GCmate mass spectrometer.
(6) Elemental analysis: Measured with PERKINELMER Series CHNS/O Analyzer 2400.
(7) Silica gel for chromatography: Wakogel C-200 (Wako Pure Chemical Industries, Ltd.), Silica Gel 60 PF254 (Nacalai Tesque, Inc.), Kieselgel 60 Art. 9385 (Merck), TLC-Kieselgel 60 Art. 11695 (Merck), Silica Gel 60 N (Kanto Chemical Co., Inc.) and SIL-60-S75 (YMC CO., LTD.) were used.
(8) Silica gel plates for preparative-TLC: Kieselgel 60 F254Art. 5715 (Merck, 0.25 mm) and Kieselgel 60 F254Art. 5744 (Merck, 0.5 mm) were used.
(9) Preparative-HPLC: JAI LC-908 was used. As columns, JAIGEL-1H, JAIGEL-2H and JAIGEL-SIL S-043-15 were used.
(10) HPLC for qualitative analysis: Shimadzu LC-10A was used. As a column, Daicel Chiral Column (CHIRALCEL OD) was used.
(11) Solvents: As an ether solvent or aromatic solvent used in each reaction, there was used one which had been made anhydrous by distilling from sodium benzophenone ketyl at the time of use. As chloroform, there was used one which had been mede anhydrous by distilling from CaCl2, after ten washings with water to remove a stabilizer ethanol at the time of use. As other anhydrous solvents, there were used those which had been made anhydrous according to a conventional method.
(12) The following abbreviations are used in the examples described below:
Ac: acetyl group, Bn; benzyl group, Bu; butyl group, Boc: t-butoxycarbonyl group, Z; benzyloxycarbonyl group, DMAP; 4-dimethylaminopyridine, Et3N; triethylamine, MeOH; methanol, THF; tetrahydrofuran, AcOEt; ethyl acetate, PLE; porcine liver esterase, PPL; porcine pancreas lipase, B.Y.; baker""s yeast, MS4A; molecular sieve 4A.